2-methyl-3,4-dihydroxy-5-phosphonoxymethyl-pyridine and method for preparing same



Patented Feb. 14, 1950 Z-METHYL- 3,4 -DIHYDROXY- 5 OXYMETHYL-PYRIDIN E-PHOSPHQN- AND METHOD FOR PREPARING SAME- Dorothea Heyl Hoffman,Railway, N. J., assignor to Merck & 00., Inc., Rahway, ration of NewJersey N. .I., a corpo- No Drawing. Application July 9, 1947, SerialNo.759,909

(Cl. 260-297 I 2 Claims.

This invention relates to novel chemical compounds, and processes ofpreparing the same. More particularly, it is concerned with Z-methyl-3,4-dihydroxy-5-hydroxymethylpyridine and esters thereof.

These novel chemical compounds possess vitamin Be activity and in smallquantities give very deep colors varying from red to purple with ferricsalts. These colored compounds may be used as inks, dyes or as a meansof determining traces of ferric iron in solution. Colored chelates arealso obtained with other metals, such as copper. These novel compoundsare also capable of coupling with diazonium hydroxides from aniline,p-aminobenzoic acid, etc., to give red dyes.

The compounds forming the subject matter of the present invention may berepresented graphically as follows:

RO- OHaOR' wherein R, represents hydrogen and p-toluenesultony] groupand R represents hydrogen, phosphono, calcium phosphono andp-toluenesulfonyl substituents.

It has now been discovered in accordance with. the present inventionthat compounds of the above formula wherein R and R. are hydrogen, fullydefined by the chemical name Z-methyl-3,4-dihydroxy-5-hydroxymethy1pyridine, can be prepared by reacting2-methy1-3-hydroxy-4- I0rmyl 5-hydroxymethylpyridine with hydrogenperoxide in an aqueous alkaline medium.

Various esters of 2-methyl-3,4-dihydroxy-5- hydroxymethylpyridine suchas the phosphate of the fi-hydroxymethyl, and p-toluenesulfonate estersof the 3-hydroxy-5-hydroxymethy1 groups have now been prepared. Aprocess for preparing 2-methyl-3,4-dihydroxy 5 phosphonoxymethylpyridineinvolves reacting 2-methyl-3,4- dihydroxy-5-hydroxymethylpyridinesuccessively with phosphorus oxyhalide and calcium carbonate in aqueousmedium, recovering the calcium salt of2-methyl-3,4-dihydroxy-5-phosphonoxy methylpyridine and reacting thelatter compound with hydrochloric acid to form 2-methyl3,4-dihydroxy-5-phosphonoxymethylpyridine.

An alternative method for preparing Z-methyl-3,4-dihydroxy-5-phosphonoxymethylpyridine involves reacting the calciumsalt of 2-methyl-3- hydroxy-4-formyl- 5-phosphonoxymethylpyridine withsodium hydroxide and hydrogen peroxide.

The 2-methyl-3,4-dihydroxy-5-hydroxymethylpyridine can be converted tothe p-toluenesulfonyl ester byreacting Z-methyl-3,4-dihydroxy-5-hydroxymethyl-pyridine with p-toluene sulfonylchloride. in a pyridinemedium and recovering 2-methyl-B-p-toluenesulfonoxy-4-hydroxy- 5hydroxymethylpyridine and 2-methyl-3-p-toluenesulfonoxy-4-hydroxy-5-ptoluenesulfonoxymethylpyridine by fractional crystallization.

This process can be represented graphically as, follows:

CHO

H0 CHiOPOiCh I N I lNnOH H103 arm on on on no onion no onion Pooh noomoroica H0] H0 amorous,

-o me me Cw mo Hi0 N N N Pyridine omotmsoiol J g, on cmmmsmo onioncmcimsoio GEO-5010084011:

in carrying out the process of the present invention, 2 methyl 3hydroxy-4-formyl-5-hydroxymethylpyridine hydrochloride is dissolved inwater. The solution is cooled and adjusted to pH 10. The mixturecontaining the free base,

2-methyl-3-hydroxyi-formyl-5-hydroxymethylpyridine is then reacted withhydrogen peroxide. The mixture is cooled, acidified and 2-methy1-3,4-dihydroxy-5-hydroxymethylpyridine crystals separate from solution.

These crystals are recovered and suspendedin water. The aqueous solutionis treated first with phosphorus oxychloride and later with calciumcarbonate. The precipitate of the calcium salt of2-methyl-3,4-dihydroxy-5-phosphonoxymethylpyridine is recovered. Thecalcium salt is suspended in water, the solution adjusted to pH 2 and 2methyl-BA-dihydroxy-5.phosphonoxymethyl pyridine crystals separate fromsolution.

The alternative process for preparing 2-methyl3,4-dihydroxy-5-phosphonoxymethylpyridine involves reacting2-methyl-3-hydroxy-4-formyl- 5-calcium phosphonoxymethylpyridine withsodium hydroxide and hydrogen peroxide.

The p-toluenesulfonyl esters can be prepared by reacting2-methyl-3A-dihydroxy-5-hydroxymethylpyridine with p-toluenesulfonylchloride in a .pyridine medium. Cold water is added to the thecalcium mixture which resulted in the formation of an oil.2-methyl-3-p-toluenesulfonoxy-i-hydroxyfi-hydroxymethylpyridinecrystallized after ether had been added to the mixture. Cooling of theaqueous mother liquor resulted in the crystallization of 2 methyl3-p-toluenesulionoxy i-hydroxy-5-p-toluenesulfonoxymethylpyridine.

The following examples illustrate a method of carrying out the presentinvention, but it is to be understood that these examples are given byway 3f illustration and not of limitation.

' Example 1 5.0 g. of2-methy1-3-hydroxy-4'-fprrnyl-5-hydroxymethylpyridine hydrochloride wasdissolved in 15 cc. of water. The solutionwas cooled in an ice bath andsufficient 6 N sodium hydroxide was added to adjust the solution to pH10. The bright yellow mixture thus formed was removed from the ice bathand hydrogen peroxide (30%) was added, several drops at a time. Afterabout 5 cc. of the hydrogen peroxide had been added, the mixture becamealmost colorless. The mixture was then cooled in an ice bath and thesolution acidified to pH 5 with hydrochloric acid. After furthercooling, crystals of 2-methyl-3,4- dihydroxy-5-hydroxymethylpyridineseparated from solution. The mixture was filtered and the crystalswashed successively with water, alcohol and ether. The crystals had amelting point of 2255-2265 C. with decomposition. Two recrystallizationsfrom water did not change the melting point. This material gave a purplecolor with ferric chloride solution.

Anal. Calcd. for. C7H9NO3Z C, 54.16; H, 5.85; N,-

9.03. Found: C, 54.40; H, 5.94; N, 8.97.

Example 2 stirring and removal of excess hydrogen chloride The rate ofaddition was regulated so.

under reduced pressure, the mixture was surrounded by a, water bath at 5C. A suspension of calcium carbonate in water was added until the colorturned pink, carbon dioxide was no longer evolved, and the solution waspH 5. After an hour of chilling, the precipitate was removed byfiltration and washed with ice water. The aqueous solution, totaling 15000., was diluted. with three volumes of alcohol. After 2 hours ofcooling, the pink precipitate of the calcium salt of2-methyl-3,4-dihydroxy-5-phosphonoxymethylpyridine was centrifuged andwashed twice with alcohol and once with ether.

The calcium salt described above was suspended in water, cooled in ice,and suificient 6 Example*.?

A saturated oxalic acid solution was added dropwise with thoroughstirring to 100 mg. of

salt of 2-methyl-3-hydroxy-4- formyl 5 phosphonoxymethylpyridine(estimated by assay to be about 80% pure) until the yellow solid had alldisappeared. The white precipitate of calcium oxalate was removed bycen-. trifuging and washed twice with water. The combined solution andwashings were chilled in an ice bath and made alkaline (pl-I 10) by thedropwise addition of sodium hydroxide solution. Several drops ofhydrogen peroxide (30%) was added, also dropwise, and the solutionwarmed to room temperature. The color change from bright yellow to avery pale yellow required about ten minutes. After removal of somecalcium hydroxide by centrifuging, the solution, chilled in ice, wasacidified (pH 2) with N hydrochloric acid. The2-methyl-3,l-dihydroxy-5-phosphonoxymethylpyridine crystallized promptlyfrom solution. The crystals were removed and washed successively withice water, alcohol and ether.

2 The crystals had a melting point or 229-230 C.

with decomposition and gave a purple color with ferric chloridesolution.

Anal. Calcd. for CqHroNOeP: c, 35.73; H, 4.29; N,

5.96; P, 13.19. Found: 0, 35.55; H, 4.63; N, 5.73; P, 13.00.

Example 4 mixture was cooled, filtered, and well washed sucabove 50 C.After an additional half hour of" w cessively with water, alcohol andether. The crude 2-methy1-3-toluenesulfonoxy-4-hydroxy-5-hydroxymethylpyridine was recrystallized 3 times from alcohol, thefinal product melting at 228-229 C. with decomposition.

Anal. Calcd. for C14H15NO5S2 c, 54.36; H, 4.89; N,

Found: o,54.s6;r1, 5.09; N, 4.70.

The ether was sucked oil. the filtrate from which the crude material inthe above preparation had been separated, and the aqueous solution wasdiluted with water and cooled in an ice bath. The resulting crystals of2-methyl-3-p-toluenesulfonoxy 4 hydroxy 5p-toluenesulfonoxymethylpyridine were filtered and washed successlvelywith water, alcohol and ether. After 2 recrystalllzations from alcohol,the melting point of the crystals was constant at 140.0-141.5 C.

Anal. Calcd. for C21H21NO7S22 C, 54.41; H, 4.59; N,

3.02; S, 13.83. Found: C, 54.53; H, 4.27; N, 3.25; S, 13.71.

Modifications may be made in carrying out the present invention withoutdeparting from the spirit and scope thereof and the invention is to belimited only by the appended claims.

No references cited.

1. 2-METHYL-3,4 - DIHYDROXY -5 - PHOSPHONOXYMETHYLPYRIDINE.
 2. THEPROCESS THAT COMPRISES REACTING THE CALCIUM SALT OF2-METHYL-3-HYDROXY-4-FORMYL-5PHOSPHOMOXMETHYLPYRIDINE WITH AN OXALICACID SOLUTION THEREBY PRECIPITATING CALCIUM OXALATE, REMOVING THECALCIUM OXALATE FROM SOLUTION, REACTING SAID SOLUTION WITH SODIUMHYDROXIDE AND HYDROGEN PEROXIDE, REACTING THE RESULTING SOLUTION WITHACID AND RECOVERING THE 2-METHYL-3,4DIHYDROXY-5 -PHOSPHONOXYMETHYLPYRIDINE THUS FORMED.